Surfaces form the interface between different physical and chemical entities, and the physical and chemical processes that occur at surfaces often control the bulk behavior of materials. For example, the rate of dissolution of drug particles in a biological fluid (e.g., stomach, intestinal, bronchial, or alveolar fluid in a human) can strongly influence the rate of uptake of the drug into an animal. Differences in particle size distribution between two otherwise identical compositions of the same drug can lead to significant differences in the pharmacological properties of the two compositions. Further by way of example, the surface area of a solid chemical catalyst can strongly influence the number and density of sites available for catalyzing a chemical reaction, greatly influencing the properties of the catalyst during the reaction. For these and other reasons, manufacturers often try to closely control particle size and shape. Associations between and among particles can also affect the pharmacological properties of substances in the particles, such as the ability of a substance to dissolve or become active in a biological system.
Numerous methods of analyzing particle sizes and distributions of particle sizes are known in the art, including at least optical and electron microscopy, laser diffraction, physical size exclusion, dynamic light scattering, polarized light scattering, mass spectrometric, sedimentation, focused beam backscattered light reflectance, impedance, radiofrequency migration, Doppler scattering, and other analytical techniques. Each of these techniques has a variety of limitations that preclude its use in certain situations. However, all of these techniques share a critical limitation that prevent effective use of the techniques for a wide variety of samples for which particle analysis would be valuable—namely, none of the prior art techniques is able to distinguish two particles that differ only in chemical composition. Put another way, a first particle having substantially the same size, shape, and weight as a second particle cannot be distinguished from the second particle in these methods. One method for using Raman spectroscopic methods for component particle analysis is described in U.S. Pat. No. 7,379,179 to Nelson et al., entitled “Raman Spectroscopic Methods for Component Particle Analysis”, which is hereby incorporated by reference in its entirety.
In addition to distinguishing particles based on chemical composition, it is also useful to determine particle size and particle size distribution (“PSD”). Particle sizing of Active Pharmaceutical Ingredients (“API”) and Excipients of Interest implemented using image analysis must be accurate because of the requirements of customers and the Food and Drug Administration (“FDA”). The FDA acknowledges a critical path opportunity for the development of methodologies for accurate and precise drug particle size measurements in suspension products, thereby minimizing the requirement for in vivo testing.
Batch comparison testing is an important part of product quality studies and is necessary in studying bioavailability (“BA”) and/or establishing bioequivalence (“BE”) for products including, but not limited to, nasal sprays. It is recommended by the FDA that in the BA and BE submission that PSD data is submitted for both new drugs (“NDAs”) and abbreviated new drug applications (“ANDAs”) for spray and aerosol formulations. Data must be presented prior to and post actuation since this information closely relates to the drug efficacy based on the dissolution rate of the particles. Such information can help establish the potential influence of the device on de-agglomeration.
Optical microscopy is currently the recommended method of assessing and reporting drug and aggregated drug PSD. However, such methodology is subjective and cannot be used with a high degree of confidence for formulated suspensions where drug particle sizing can be easily misjudged due to the presence of insoluble excipients.
Currently, no validated method exists for characterizing API particle size distribution in nasal aerosols and sprays dispite the request of such data for BE testing for NDAs and ANDAs. A qualitative and semi-quantitative estimation of drug and aggregated drug PSD is recommended based on optical microscopy, but insoluble suspending agents found in nasal spray formulations typically complicate the ingredient-specific particle size (“ISPS”) determination. Therefore, there exists a need for an accurate and reliable system and method for performing such analysis on particle samples.